This application addresses broad Challenge Area (03): Biomarker Discovery and Validation, and specific Challenge Topic 03-OD (ORDR)-101*: Validating Biomarkers for Functional Outcomes in Rare Diseases. The systemic vasculitides are a group of diseases characterized by severe inflammation of blood vessels leading to arterial stenosis or occlusion, and organ damage or death if untreated. Two related vasculitides, Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), each associated with anti-neutrophil cytoplasmic antibodies (ANCA) and notable for being organ- and life-threatening and prone to relapse after periods of remission. With aggressive immunosuppressive treatment, most patients with these ANCA- associated vasculitides (AAV) survive, but subsequent disease course is variable, relapse is common, and long-term morbidity from vasculitis or its treatment is expected. There is a significant unmet need for markers of disease activity, responsiveness to therapy, risk of relapse, and long-term damage. Accurate markers would be of great benefit in detecting flares early to prevent acute and chronic morbidities, avoiding over-treatment, and measuring response to treatment in practice, early-phase proof-of-concept treatment studies, and larger trials. Two studies now offer an unprecedented opportunity to accelerate discovery of useful biomarkers in patients with AAV, due to their large and already established cohorts, comprehensive clinical data collection systems, repositories of biological specimens linked to each visit, and longitudinal nature: the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Studies, and the Rituximab in ANCA-Associated Vasculitis (RAVE) clinical trial. The value of these repositories is evidenced by the interest that basic science investigators have expressed in collaboration. Plans are presented for ground-breaking studies on biomarkers of platelet activation, vascular inflammation and immunology, endothelial damage, and epitope-specific ANCA subsets. These studies will identify and validate markers of active vasculitis and markers predictive of future flare or remission. The work proposed is fully consistent with the goals of NIH funding through the American Recovery and Reinvestment Act of 2009: All of the materials and expertise necessary to conduct these studies are ready and available for immediate use ("shovel ready") and the funds would be used quickly and efficiently to create and retain jobs in US academic medical centers. The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis. PUBLIC HEALTH RELEVANCE: The proposed studies will identify biomarkers circulating in the blood, measurement of which will assist clinicians in the care of patients with ANCA-associated vasculitis, a set of rare, severe diseases of inflammation of blood vessels. Results of these studies will also be important in the design of future clinical trials in these rare but important diseases and will provide insight into biomarker development in other types of vasculitis.